352

Additive-assisted regioselective 1,3-dipolarcycloaddition of azomethine ylides

with benzylideneacetoneChuqin Peng, Jiwei Ren, Jun-An Xiao, Honggang Zhang, Hua Yang*§

and Yiming Luo*¶

Letter Open Access

Address:School of Chemistry and Chemical Engineering, Central SouthUniversity,Changsha, Hunan 410083, P. R. China

Email:Hua Yang* - hyangchem@csu.edu.cn; Yiming Luo* -ymluo@csu.edu.cn

* Corresponding author§ Tel.: +86-731-88830833¶ Tel.: +86-731-88864409

Keywords:1,3-dipolar cycloaddition; azomethine ylide; regioselectivity;spirooxindole

Beilstein J. Org. Chem. 2014, 10, 352–360.doi:10.3762/bjoc.10.33

Received: 22 November 2013Accepted: 16 January 2014Published: 07 February 2014

Associate Editor: C. Stephenson

© 2014 Peng et al; licensee Beilstein-Institut.License and terms: see end of document.

Abstract1,3-Dipolar cycloadditions of isatins, benzylamine and benzylideneacetones were studied to prepare a series of novel spiropyrroli-

dine-oxindoles – 4′-acetyl-3′,5′-diarylspiro[indoline-3,2′-pyrrolidin]-2-ones and 3′-acetyl-4′,5′-diarylspiro[indoline-3,2′-

pyrrolidine]-2-ones in good yields of up to 94% and with good regioselectivities. Regioselectivities are reversible by the addition of

water or 4-nitrobenzoic acid, respectively. The substituent effects on the regioselectivity were also investigated.

352

IntroductionSpirooxindoles are important synthetic targets due to their

significant biological activities and their applications for phar-

maceutical lead discovery. These compounds are the central

skeleton of numerous alkaloids [1-8] and have found wide bio-

logical applications, e.g., as potent p53–MDM2 inhibitors

[9-15]. Usually, isatin and its derivatives were employed as

starting materials to conduct 1,3-dipolar cycloadditions to yield

spirooxindole core structures [16-20]. Owing to the ease of

preparation, the azomethine ylides generated from isatin with

α-amino acids or amines were frequently chosen as important

1,3-dipolar intermediates to react with various dipolarophiles,

such as α,β-unsaturated esters [21-25], dienones [26,27], α,β-

unsaturated ketones [28-30], unsaturated aryl ketones [31-33]

and electron-poor alkenes [34-39].

Among the studied α,β-unsaturated enones for 1,3-dipolar

cycloaddition, chalcone derivatives are the most widely used

dipolarophiles. Sarrafi and co-workers reported a 1,3-dipolar

Beilstein J. Org. Chem. 2014, 10, 352–360.

353

Scheme 1: Different regioselectivities in 1,3-dipolar cycloaddition of azomethine ylide.

cycloaddition reaction of isatin, benzylamine and chalcone

derivatives [31], and only one single regioisomer was obtained

in high yield, in which the benzoyl group was connected to C-3

of the newly-constructed pyrrolidine. However, unsaturated

ketones with α-hydrogens such as benzylideneacetone, which

have attracted great interest due to their synthetic potential [40-

42], have not been exhaustively studied as suitable dipo-

larophiles for 1,3-dipolar cycloadditions of azomethine ylides to

prepare spirooxindoles yet [43]. Therefore, extensive studies on

the regioselective 1,3-dipolar cycloaddition of azomethine

ylides using simple unsaturated ketones, especially ketones

having α-hydrogens, are highly desirable, to enrich the library

of spirooxindoles and facilitate their biological investigations.

Our group recently reported an unusual regioselectivity when

3-acetonylideneoxindoles were employed as dipolarophiles to

react with azomethine ylides [44]. The structure of the sub-

strate significantly affected the regioselectivity of the 1,3-

dipolar cycloaddition, which allowed the formation of 3-acetyl-

5-phenyl-pyrrolo(spiro-[2.3′]-1′-benzyloxindole)-spiro-[4.3″]-

1″-benzyloxindoles in good regioselectivity. Our continued

interest in the regioselective 1,3-dipolar cycloaddition of

azomethine ylides prompted us to further investigate the regio-

selectivity of the 1,3-dipolar cycloaddition using α,β-unsatu-

rated enones. Moreover, we envisioned that the additive might

effectively tune the regioselectivity of a 1,3-dipolar cycloaddi-

tion of azomethine ylide. Herein, we report a three-component

1,3-dipolar cycloaddition of azomethine ylides, generated in

situ from isatin derivatives and benzylamine, with benzylidene-

acetone derivatives in the presence of various additives. It was

found that the addition of water can significantly improve the

regioselectivity and yield of this reaction [45-48]. More impor-

tantly, the regioselectivity of the 1,3-dipolar cycloaddition of

azomethine ylide was reversed by the addition of 4-nitroben-

zoic acid, which led to the formation of spirooxindoles with

novel substitution patterns (Scheme 1). Accordingly, a series of

novel functionalized 3-spiropyrrolidine-oxindoles bearing an

acetyl group were prepared via this 1,3-dipolar cycloaddition

with up to 94% yield. To the best of our knowledge, the reversal

of the regioselectivity in the 1,3-dipolar cycloaddition of

azomethine ylide induced by the additive is reported for the first

time.

Results and DiscussionInitially, a three-component reaction of isatin (1a), benzyl-

amine (2) and benzylideneacetone (3a) was conducted in

ethanol at room temperature (Table 1). It smoothly went until

completion. Interestingly, the two regioisomers 4a and 5a were

obtained with modest yield and poor regioisomeric ratio

(Table 1, entry 1), which is quite different from the reaction of

chalcone. Generally, only a single regioisomer 4 ′,5 ′-

diarylspiro(indoline-3,2′-pyrrolidin)-2-one was formed when

using chalcone or dienone as dipolarophiles [20,31]. Presum-

ably, this might be attributed to the electronic and steric effects

of the acetyl group. Therefore, reaction conditions including

various solvents and additives (Table 1, entries 2–9) were

screened to improve the regioselectivity in this reaction. It

turned out that the addition of triethylamine or the removal of

water by using molecular sieves slightly decreased both the

yield and the regioisomeric ratio (Table 1, entry 2 and entry 3).

Beilstein J. Org. Chem. 2014, 10, 352–360.

354

Table 1: 1,3-Dipolar cycloaddition reaction of isatin (1a) and benzylamine (2) with benzylideneacetone (3a)a.

Entry Solventb Additive Time (h) Yield (%)c Regioisomeric ratio (4a/5a)d

1 EtOH – 48 72 75:252 EtOH Et3N (0.2 equiv) 72 69 78:223 EtOH 4 Å MS 48 59 76:244 EtOH 4-NO2PhCO2H (0.2 equiv) 24 33 50:505 EtOH H2O (5.0 equiv) 24 54 83:176 EtOH H2O (20 equiv) 24 52 76:247 EtOH EtOH:H2O (1:1) 24 50 75:258 H2O – 72 23 68:329 DMF H2O (5.0 equiv) 18 78 84:1610 CH3CN H2O (5.0 equiv) 48 56 67:3311 THF H2O (5.0 equiv) 24 71 86:1412e THF H2O (5.0 equiv) 24 88 86:14

aUnless otherwise noted, all reactions were carried out in sealed reaction vials at rt with isatin (1a, 0.50 mmol), benzylamine (2, 1.0 mmol), benzyl-ideneacetone (3a, 0.75 mmol), and additives in solvent (5.0 mL). bAnhydrous solvent was used. cCombined yield of isolated 4a and 5a. dThe regio-isomeric ratio was determined by the isolated yields of 4a and 5a. eThe ratio of 1a/2/3a is 1.5:2:1.

However, the incorporation of 4-nitrobenzoic acid can favor the

formation of regioisomer 5a with a regioisomeric ratio of 50:50

(Table 1, entry 4). Interestingly, the employment of water as an

additive resulted in a significant improvement of the regio-

isomeric ratio and a slightly decreased yield (Table 1, entry 6).

Encouraged by this result, we studied the effect of the amount

of water on the regioselectivity. When the amount of water was

increased to 5.0 equiv, the ratio of 4a/5a could be improved to

83:17 (Table 1, entry 5). Meanwhile, as the addition of water

was further increased (from 5.0 equiv to 1:1, Table 1, entry 6

and entry 7), the regioisomeric ratio dropped slightly and

leveled off. The use of water as a solvent led to a poor yield

with eroded regioselectivity (Table 1, entry 8). Various solvents

with 5.0 equiv of water as an additive were subsequently

investigated. The best regioselectivity was obtained with THF

as a solvent (Table 1, entries 9–11). The amount of isatin is also

important for the yield, and the yield was improved to 88%

when 1.5 equiv of isatin were used (Table 1, entry 12). This

might be due to the instability of the corresponding azomethine

ylides, and an excess of isatin and benzylamine was therefore

needed.

As shown in Table 1 (entry 4), the addition of acid facilitated

the formation of regioisomer 5a, which prompted us to further

investigate the effects of acid additives. We anticipated that the

acid additives might lead to the preferably formation of regio-

isomer 5a, which would provide us an efficient pathway to

prepare the spirooxindoles with this novel substitution pattern.

Thus, the acid additives were examined and the optimization

results are listed in Table 2. To our delight, the addition of

4-nitrobenzoic acid reversed the regioselectivity of this reaction,

and the ratio of 5a/4a was increased from 50:50 to 70:30 with

an improved yield (90%) when the amount of 4-nitrobenzoic

acid increased from 0.2 equiv to 2.0 equiv (Table 2, entries

1–5). Presumably, this might be attributed to the acid, which

accelerates the formation of azomethine ylide. However, a large

excess of acid (10 equiv) has a detrimental effect on the reac-

tion, and the yield of 4a and 5a dropped tremendously to 46%

(Table 2, entry 6 and entry 7). As a result, 2.0 equiv of

4-nitrobenzoic acid proved to give superior results. Various acid

additives were also evaluated. Unfortunately, the corres-

ponding azomethine ylides were not formed as indicated by

TLC, and cyclization was not observed with 2.0 equiv p-TSA

and TFA (Table 2, entry 8 and entry 9). Both the benzoic acid

and acetic acid slightly improved the formation of regioisomer

5a (Table 2, entry 10 and entry 11). Additionally, a cycloaddi-

tion product was not observed with acetic acid as a solvent

(Table 2, entry 12).

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Table 2: 1,3-Dipolar cycloaddition reaction of isatin (1a) and benzylamine (2) with benzylideneacetone (3a) and acid additivesa.

Entry Additive Solventb Time (h) Yield (%)c Regioisomeric ratio (4a/5a)d

1 4-NO2PhCO2H (0.2 equiv) THF 12 33 50:502 4-NO2PhCO2H (0.5 equiv) THF 12 69 42:583 4-NO2PhCO2H (1.0 equiv) THF 12 62 32:684 4-NO2PhCO2H (1.5 equiv) THF 12 79 31:695 4-NO2PhCO2H (2.0 equiv) THF 12 90 30:706 4-NO2PhCO2H (5.0 equiv) THF 12 75 30:707 4-NO2PhCO2H (10.0 equiv) THF 12 46 37:638 p-TSA (2.0 equiv) THF 48 trace9 TFA (2.0 equiv) THF 48 trace10 PhCO2H (2.0 equiv) THF 12 75 54:4611 AcOH (2.0 equiv) THF 12 85 69:3112 – AcOH 48 trace

aUnless otherwise noted, all reactions were carried out in sealed reaction vials with isatin (1a, 0.75 mmol), benzylamine (2, 1.0 mmol), benzylidene-acetone (3a, 0.50 mmol) and additives in solvent (5.0 mL) at rt. bAnhydrous solvent was used. cCombined yield of isolated 4a and 5a. dThe regio-isomeric ratio was determined by the isolated yields of 4a and 5a.

A plausible mechanism for the regioselectivity in this transfor-

mation is proposed in Scheme 2. The azomethine ylides gener-

ated from the reaction of isatin with benzylamine has two

potential nucleophilic carbons (6a and 6b) [34], each of which

could add to the electron-deficient β-carbon of benzylidene-

acetone during the cycloaddition leading to two regioisomers

[31]. In the presence of water, transition state A is favored due

to the formation of an intermolecular hydrogen bonding

between water and two carbonyl groups in the reaction

substrates, while transition state B suffers from severe steric

repulsion [45-48]. Presumably, the addition of 4-nitrobenzoic

acid might facilitate the formation of dipole 6b. Similarly, the

less sterically hindered transition state C leads to 5a as the

major product. Further research work on the elaboration of the

detailed mechanism is still underway and will be published in

due course.

Having established the optimal protocol for this reaction, we

next examined the scope of this method with regard to α,β-

unsaturated ketones and azomethine ylides. With the aim of

applying this additive-assisted regioselective 1,3-dipolar cyclo-

addition to prepare two regioisomers in high yields, we tested

two reaction conditions (conditions A: 5.0 equiv H2O as an

additive; conditions B: 2.0 equiv 4-NO2PhCOOH as additive)

for all substrates. As shown in Table 3, the reactions between

benzylideneacetone with the azomethine ylides derived from

isatin 1a–e and benzylamine (2) proceeded smoothly to furnish

the desired products with good yields. The opposite regioselec-

tivities were also observed by using water and 4-nitrobenzoic

acid as additives, respectively (Table 3, entries 1–5). The

substituents on the phenyl ring of isatin exert a mild influence

on the regioselectivities, resulting in slightly lowered yields and

regioseletivities (Table 3, entries 2–5). Next, benzylidene-

acetone derivatives 3a–g were employed to react with the

azomethine ylide derived from isatin (1a) and benzylamine (2).

It was found that the electronic nature of the substituent and its

position on the benzylideneacetone aromatic ring significantly

influenced the regioisomeric ratio. In general, the regioisomeric

ratio with water as an additive is comparatively higher for the

substrates in which the phenyl rings of enones were substituted

by electron-donating groups (Table 3, entries 6, 10 and 11).

When the hydroxy group was introduced to the para-position

on the phenyl ring of enone, the best regioisomeric ratio was

obtained and only one single regioisomer 4k was isolated

(Table 3, entry 11). Surprisingly, the addition of 4-nitrobenzoic

acid only slightly facilitated the formation of regioisomers

Beilstein J. Org. Chem. 2014, 10, 352–360.

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Scheme 2: Plausible pathways for the formation of different regioisomers.

Beilstein J. Org. Chem. 2014, 10, 352–360.

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Table 3: 1,3-Dipolar cycloaddition reaction of isatin derivatives 1a–e and benzylamine (2) with benzylideneacetone derivatives 3a–ga.

Entry R Ar Product Conditions (A or B)b Yield (%)c Regioisomeric ratio(4a–l/5a–l)d

1 H Ph 4a + 5aA 88 86:14B 90 30:70

2 5-F Ph 4b + 5bA 79 74:26B 92 38:62

3 5-Me Ph 4c + 5cA 88 68:32B 89 31:69

4 5-Cl Ph 4d + 5dA 69 73:27B 67 32:68

5 6-Br Ph 4e + 5eA 77 80:20B 80 24:76

6 H o-OHC6H4 4f + 5fA 86 85:15B 80 11:89

7 H 2-Py 4g + 5gA 90 81:19e

B 84 40:60e

8 H o-NO2C6H4 4h + 5hA 92 67:33B 85 55:45

9 H p-NO2C6H4 4i + 5iA 93 70:30B 84 58:42

10 H o-CH3C6H4 4j + 5jA 92 78:22B 93 60:40

11 H p-OHC6H4 4k + 5kA 94 97:3e

B 82 99:1e

aUnless otherwise noted, all reactions were carried out in sealed reaction vials at rt with isatin derivatives 1a–e (0.75 mmol), benzylamine (2,1.0 mmol), benzylideneacetone derivatives 3a–g (0.50 mmol), and additives in THF (5.0 mL) for 48 h. bConditions A: 5.0 equiv H2O (2.5 mmol) asadditive; conditions B: 2.0 equiv 4-NO2PhCOOH (1.0 mmol) as additive. cCombined yield of isolated 4a–k and 5a–k. dThe regioisomeric ratio wasdetermined by the isolated yields of 4a–k and 5a-k. eThe regioisomeric ratio was determined by 1H NMR of the crude mixture.

5h–5j (Table 3, entries 8–11) and did not yield the reversed

regioselectivities. Notably, the regioisomer 5k was present in

trace amounts, even after the addition of 4-nitrobenzoic acid.

Finally, the structures and relative configurations of the

cycloadducts 4e and 5e were unequivocally determined by an

X-ray crystallographic analysis of a single crystal (Figure 1 and

Figure 2).

ConclusionIn summary, we herein described an additive-assisted

regioselective 1,3-dipolar cycloaddition reaction of azomethine

ylide to synthesize novel functionalized spirooxindoles

in good to excellent chemical yields with good regioselectivi-

ties. Furthermore, the regioselectivity can be conveniently

tuned and reversed by simply adding water or 4-nitrobenzoic

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358

Figure 1: ORTEP diagram of 4e.

Figure 2: ORTEP diagram of 5e.

acid, which provides a facile approach to access a wide

range of spirooxindole ring systems with novel substitution

patterns.

Supporting InformationSupporting Information File 1Experimental procedures, characterization data and copies

of 1H and 13C NMR spectra.

[http://www.beilstein-journals.org/bjoc/content/

supplementary/1860-5397-10-33-S1.pdf]

AcknowledgementsWe gratefully acknowledge the financial support from the

Central South University, the National Natural Science Founda-

tion of China (21276282 & 21376270), and the Hunan Provin-

cial Science & Technology Department (2012WK2007).

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